Quinazoline deriviates for treating peptic ulcer

ABSTRACT

A quinazoline derivative represented by formula(I) or a pharmaceutically acceptable salt thereof is useful for the treatment of peptic ulcer, wherein: ##STR1## R 1  and R 2  are each hydrogen or a C 1  -C 4  alkyl group; R 3  is hydrogen or a halogen; 
     R 4 , R 5 , R 6 , R 7 , R 8  and R 9 , which may be the same or different, are each hydrogen, a C 1  -C 4  alkyl group, a cyclopropyl group, or a C 1  -C 4  alkyl group substituted with a halogen; and 
     R 10  is a methoxy group.

This is a 371 of PCT/KR93/00096 filed Oct. 29, 1993.

FIELD OF THE INVENTION

The present invention relates to novel quinazoline derivatives andpharmaceutically acceptable salts thereof which possess an excellentanti-secretory activity, pharmaceutical compositions containing the sameas an active ingredient, their novel intermediates, and processes forthe preparation thereof.

BACKGROUND OF THE INVENTION

For the treatment of peptic ulcer disease, various drugs such asantacid, anticholinergic agent and H₂ -receptor antagonist have beenused. Recently, the advent of omeprazole useful as a proton pumpinhibitor has rekindled research activities in this field.

However, it has been pointed out that the proton pump inhibition byomeprazole is irreversible, which may induce side effects. Accordingly,various attempts to develop a reversible proton pump inhibitor are beingactively made. For example, European Patent Nos. 322133 and 404322disclose quinazoline derivatives involving a reversible proton pumpinhibitor.

SUMMARY OF THE INVENTION

The present inventors have carried out extensive research to develop areversible proton pump inhibitor with improved efficacy; and, as aresult, have discovered that quinazoline derivatives having atetrahydroisoquinoline group at the 4-position of the quinazolinenucleus exhibit excellent proton pump inhibition effects and have theability to attain a reversible proton pump inhibition.

Accordingly, it is an object of the present invention to provide novelquinazoline derivatives having a tetrahydroisoquinoline group at the4-position of the quinazoline nucleus, and pharmaceutically acceptablesalts thereof.

It is another object of the present invention to provide processes forpreparing said compounds.

It is a further object of the present invention to providepharmaceutical compositions containing the same as active ingredients.

It is still another object of the invention to provide novelintermediate compounds useful for the preparation of the inventivequinazoline derivatives.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be more fully understood with reference to thefollowing drawings, wherein:

FIGS. 1 to 3 depict the Lineweaver-Burk plots of the specific activitiesobtained from an exemplary inventive compound, omeprazole and SK&F96067.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided novelquinazaline derivatives of formula(I) and their pharmaceuticallyacceptable salts: ##STR2## wherein, R₁ and R₂ are each hydrogen or a C₁-C₄ alkyl group;

R₃ is hydrogen or a halogen;

R₄, R₅, R₆, R₇, R₈ and R₉, which may be the same or different, are eachhydrogen, a C₁ -C₄ alkyl group, a cyclopropyl group, or a C₁ -C₄ alkylgroup substituted with a halogen;

and R₁₀ is a methoxy group.

Among the compounds of the present invention, preferred are thosewherein;

R¹ and R₂ are C_(1-C) ₄ alkyl group;

R₃ is halogen;

R₄, R₅, R₆, R₇, R₈ and R₉, which may be the same or different, hydrogen,a C₁ -C₄ alkyl group or a C₁ -C₄ alkyl group substituted with a halogen.

R₁₀ is C₁ -C₄ alkoxy.

Particularly, preferred compounds of the present invention are listedbelow:

2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(N-phenylmethylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-N-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1,8-ethano-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluoro-2-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluoro-N-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

(R)-8-methoxy-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

(S)-8-methoxy-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-(2-hydroxyethyloxy)-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-ethoxy-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-(methylthiomethyloxy)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluoro-N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(1-fluoromethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-fluoromethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluorophenylamino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(2-methyl-4-fluorophenylamino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(3-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(3-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluorophenylamino)-8-methoxy-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluorophenylamino)-4-(1,8-ethano-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;

8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1,8-ethano-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline;and

2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazoline.

The quinazoline derivatives of formula(I) in the present invention mayexist in the form of an optical isomer, (R) or (S), or a mixturethereof. Both types of the isomeric compounds are found to exhibitexcellent anti-secretory activity.

The compound of formula(I) may be prepared by a process which comprisesreacting a compound of formula(II) with a compound of formula(III) togive a compound of formula(IV), which is then reacted with a compound offormula(V), as follows: ##STR3## wherein, R₁ and R₂ are each hydrogen ora C₁ -C₄ alkyl group;

R₃ is hydrogen or a halogen;

R₄, R₅, R₆, R₇, R₈ and R₉, which may be the same or different, are eachhydrogen, a C₁ -C₄ alkyl group, a cyclopropyl group, or a C₁ -C₄ alkylgroup substituted with a halogen;

R₁₀ is a methoxy group.

The compounds of formula(II) may be prepared in accordance with a knownmethod, e.g., the one disclosed in European Patent No. 0322133. Further,the compounds of formula(V) are commercially available(for exampleAldrich Co. in U.S.A.)

The compounds of formula(II) are reacted with the compounds offormula(III) in an appropriate solvent and a base for 1 to 24 hours togive the compounds of formula (IV). Suitable solvents for this reactionmay include dichloromethane, acetone, acetonitrile, dimethylformamidetetrahydrofuran and a mixture thereof with water. The reactiontemperature is preferably between a room temperature and 150° C.Suitable bases for this reaction may include triethylamine,N,N-dimethylaniline and pyridine.

The compounds of formula(IV) thus obtained are then reacted with thecompounds of formula(V) in an appropriate solvent for 2 to 4 hours togive the present compounds of formula(I). Suitable solvents for thisreaction may include dimethylformamide, p-dioxane, dimethylsulfoxide andthe like. The reaction temperature is preferably between 80° and 120° C.

The compounds of formula(IV) prepared as above are novel and useful asan intermediate for the preparation of the quinazoline compounds offormula(I). Therefore, the present invention encompasses, within itsscope, the novel compounds of formula(IV) and processes for thepreparation thereof.

The compounds of the present invention may be administered, eitherorally or intraperitoneally, in an effective amount ranging from 0.1mg/kg to 500 mg/kg, preferably from 1.0 mg/kg to 100 mg/kg into asubject patient per day.

The present invention further includes, within its scope,pharmaceutically acceptable salts of the compounds of formula(I). Thenon-toxic salts which fall within the scope of the present invention mayinclude inorganic acid salts such as hydrochloride, sulfate, phosphateand nitrate, and organic acid salts such as tartrate, fumarate, citrate,mesylate and acetate.

The pharmaceutically acceptable salts may be prepared in accordance witha known method, e.g., by reacting the compounds of formula(I) with theacids mentioned above in the presence of a solvent, e.g., methane,ethane, dichloromethane, ethyl acetate and diethyl ether.

The present invention also includes within its scope pharmaceuticalcompositions comprising one or more of the inventive compounds as aactive ingredient, in association with a pharmaceutically acceptablecarrier, excipient and/or other additives, if necessary. The activeingredient present in the composition may range from 0.1% to 99.9% byweight thereof.

The following Examples are given for the purpose of illustration only,and are not intended to limit the scope of the invention.

PREPARATION 1 Preparation of Substituted 1,2,3,4-Tetrahydroisoquinolineof Formula(III) Preparation 1-1: 1-Methyl-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of N-(2-Phenylethyl)Acetamide

12.6 ml of phenethylamine(0.1M) and 14 ml of triethylamine(0.1M) weredissolved in 100 ml of dichloro-methane; and 6.9 ml of acetylchloride(0.1M) was dropwise added thereto while maintaining thetemperature of the reaction system below 0° C., followed by stirring ata room temperature for 10 minutes. The reaction solution was washed withwater, dried over anhydrous magnesium sulfate and concentrated under areduced pressure to give 14.23 g Of the title compound as white solids.

Step 2: Preparation of 1-Methyl-3,4-Dihydroisoquinoline

8.43 g of the compound(51.6 mM) prepared in Step 1 above was added to84.36 g of polyphosporic acid, which was reacted at 160° C. for 1.5hours with stirring. The reaction solution was poured into ice water,neutralized with ammonia water, and extracted from ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and concentratedunder a reduced pressure. The residue thus obtained was subjected tosilica gel column chromatography using a mixed solvent ofmethanol:dichloromethane (1:20 (v/v)) as a developing solvent to give6.48 g of the title compound as oily substance.

Step 3: Preparation of 1-Methyl-1,2,3,4-Tetrahydroisoquinoline

1.76g of sodium borohydride(46 mM) was suspended in 80 ml of ethanol,and 6.48 g of the compound(44.6 mM) prepared in Step 2 above was addedthereto. The resultant mixture was stirred at an ambient temperature foran hour and cooled to below 5° C., which was then acidified by addingdilute hydrochloric acid. After making the reaction solution alkaline byadding sodium hydroxide, it was extracted from ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedunder a reduced pressure to give 6.17 g of the title compound as oilysubstance.

Preparation 1-2: (R)-1-Methyl-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of(R)-1-Methyl-4-Methylthio-1,2,3,4-Tetrahydroisoquinoline-3-One

27.85 ml of (R)-1-phenylethylamime(0.21M) and 30 ml oftriethylamine(0.21M) were dissolved in 200 ml of dichloromethane andcooled to 0° C. 37.8 g of α-chloro-α-(methylthio)-acetyl chloride(0.21M)was dropwise added thereto at 0° C. The resultant was stirred at roomtemperature for 30 minutes, added with tin(IV) chloride and, furtherstirred for 30 minutes at room temperature.

The reaction solution was poured into ice water and washed with water.The organic layer was dehydrated and concentrated to give 32.5 g of thetitle compound in solid form.

Step 2: Preparation of (R)-1-Methyl-1,2,3,4-Tetrahydroisoquinoline-3-One

150 g of Raney nickel was suspended in 300 ml of ethanol and 32.5 g ofthe compound(0.16M) prepared in Step 1 above was added thereto. Afterstirring the mixture at room temperature for 3 days, the Raney nickelwas removed by the filtration, and the filtrate was concentrated to give20 g of the title compound in solid form.

Step 3: Preparation of (R)-1-Methyl-1,2,3,4-Tetrahydroisoquinoline

10.0 g of the compound(62 mM) prepared by Step 2 above and 20 ml oftetrahydrofuran were mixed, and 9 ml of 10.2M borane-methylsulfidecomplex was dropwise added thereto. The mixture was reacted under refluxfor an hour and cooled to room temperature. By adding 10 ml of 6N HCl tothe reaction solution, the remaining borane-methylsulfide complex wasdestroyed and the resultant was neutralized with 10% NaOH. The reactionsolution was extracted from ethyl acetate, dehydrated and concentratedto give 8.8 g of the title compound in oil form.

Preparation 1-3: (S)-1-Methyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-2, exceptthat 25.6 ml of (S)-1-phenylethyl-amine(0.20M) and 34.8 g ofα-chloro-α-(methylthio)-acetyl chloride(0.22M) were used as startingmaterials, 8.8 g of the title compound was obtained in oil form.

Preparation 1-4: 1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of 3,4-Dihydroisoquinoline

18.8 ml of 1,2,3,4-tetrahydroisoquinoline(0.15M) was dissolved in 400 mlof dichloromethane; and 29.4 g of N-bromosuccinimide(0.165M) was slowlyadded thereto at room temperature followed by stirring for 30 minutes.To this, 100 ml of aqueous sodium hydroxide(30%) was added and furtherstirred for an hour. The organic layer was separated, washed with waterand extracted from aqueous hydrochloric acid solution. Ammonia water wasadded to adjust the pH to 9; and extracted from dichloromethane, washedwith water, dried over anhydrous sodium sulfate and concentrated to give18.5 g of the title compound in oil form.

Step 2: Preparation of 1,2,3,4-Tetrahydroisoquinoline-1-Acetic Acid

A mixture containing 18.5 g of the compound(0.14M) prepared in Step 1above and 14.5 g of malonic acid(0.14M) was stirred at 120° C. for anhour and cooled to room temperature. Thereto, a mixture solution ofmethanol and water(4:1) was added, stirred and filtered to give 11.2 gof the title compound.

Step 3: Preparation ofN-(Methoxycarbonyl)-1,2,3,8a-Tetra-HydroxychloropentIsoquinoline-7(8H)-One

11.16 g of phosphorous pentoxide was dissolved in 75.35 ml of methanesulfonic acid and heated to 150° C.; and 11.16 g of the compound(58.3mM) prepared in Step 2 was added thereto. The reaction solution wasstirred at 150° C. for 30 minutes and, then cooled to room temperature,which was added with 1.51 of 1N sodium hydroxide and extracted fromdichloromethane. The extract thus obtained was dried over potassiumcarbonate and 8.94 ml of methyl chloro-formate was added thereto, whichwas stirred for an hour, concentrated and purified by silica gel columnchromatography to give 7.2 g of the title compound.

Step 4: Preparation ofN-(Methoxycarbonyl)-1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline

7.2 g of the compound(31.3 mM) prepared in Step 3 above was dissolved in100 ml of acetic acid and subjected to hydrogenation by using 1 g of 10%palladium/active carbon as a catalyst. The palladium/active carbon wasfiltered out and the filtrate was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography to give 5.7g of the title compound.

Step 5: Preparation of 1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline

A mixture containing 5.7 g of the compound prepared in Step 4, 340 ml ofaqueous potassium hydroxide(10%) and 340 ml of ethylene glycol washeated at 100° C. for 14 hours, cooled to room temperature and extractedfrom ethyl ether. The extract was washed with water, dried overmagnesium sulfate and concentrated under a reduced pressure to give 3.7g of the title compound.

Preparation 1-5: 1-Trifluoromethyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-1, exceptthat 25 ml of phenethylamine(0.2M) and 30 ml of anhydroustrifluoroacetic acid(0.21M) were used as starting materials, 5.4 g ofthe title compound was prepared.

Preparation 1-6: 1-Fluoromethyl-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of N-(2-Phenylethyl)Fluoroacetamide

To a mixture containing 11.7 g of fluoroacetic acid (0.15M), 27.3 ml ofdicyclohexylcarbodiimide(0.17M) and 200 ml of dichloromethane wasdropwise added 17 ml of phenethylamine(0.17M), which was stirred for 12hours. The solids produced were filtered and the filtrate was washedwith water, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give 11.9 gof the title compound as white solids.

Step 2: Preparation of 1-Fluoromethyl-3,4-Dihydroiso-Quinoline

In accordance with the same procedures as in Step 2 of Preparation 1-1,except that 11.9 g of the compound (65 mM) prepared in Step 1 above wasused as a starting material, 7.7 g of the title compound was prepared.

Step 3: Preparation of 1-fluoromethyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Step 3 of Preparation 1-1,except that 7.6 g of the compound(46 mM) prepared in Step 2 above wasused as a starting material, 7.0 g of the title compound was prepared.

Preparation 1-7: 1-Ethyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-1, exceptthat 11.3 ml of phenethylamine (90 mM) and 7.8 ml of propionylchloride(90 mM) were used as starting materials, 8.48 g of the titlecompound was prepared.

Preparation 1-8: 1-Cyclopropyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-1, exceptthat 12.5 ml of phenethylamine (0.1M) and 10 ml of cyclopropanecarbonylchloride(0.11M) were used as starting materials, 2.5 g of thetitle compound was prepared.

Preparation 1-9: 3-Methyl-1,2,3,4-Tetrahydroisoquinoline

3.0 g of 3-methylisoquinoline(21 mM) and 50 ml of methanol were mixedand 0.84 g of platinum oxide was added thereto. The mixture wassubjected to hydrogenation at 40 psi and filtered. The filtrate wasconcentrated under a reduced pressure, to give 3.3 g of the titlecompound.

Preparation 1-10: 1,1-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of 1-Methyl-N-Phenylmethyl-3,4-DihydroisoquinolineBromide

A mixture containing 20 g of the compound(0.14M) prepared in Step 2 ofPreparation 1-1, 18 ml of benzyl bromide(0.15M) and 150 ml ofacetonitrile was heated under reflux for 12 hours and cooled to roomtemperature. The solids produced were filtered and dried to give 22 g ofthe title compound.

Step 2: Preparation of1,1-Dimethyl-N-Phenylmethyl-1,2,3,4-Dihydroisoquinoline

209 of the compound(0.06M) prepared in Step 1 above and 80 ml ofanhydrous ethyl ether were mixed, and 60 ml of methyl magnesiumbromide(3.0M ethyl ether solution) was dropwise added thereto. Themixture was heated for 6 hours under reflux, cooled to room temperatureand then stirred for 12 hours. An aqueous ammonium chloride solution wasadded to the reaction solution and the organic layer was separated,dried over anhydrous sodium sulfate and concentrated under a reducedpressure. The residue produced was purified by silica gel columnchromatography to give 11.4 g of the title compound.

Step 3: Preparation of 1,1-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

11 g of the compound(44 mM) prepared in Step 2 above and 80 ml of aceticacid were mixed and 10% palladium/charcoal was added thereto, which wassubjected to hydrogenation at 40 psi and filtered. The filtrate wasconcentrated under a reduced pressure and basified with aqueous NaOHsolution. After extracting the resultant with dichloromethane, theextract was dried over anhydrous sodium sulfate and concentrated, togive 6.78 g of the title compound.

Preparation 1-11: 1,8-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

Step 1: Preparation of 1-(2'-Methylphenyl )Ethylamine

26 ml of 2-methylacetophenone(0.2M), 32 ml of formamide and 7.5 ml offormic acid were mixed and reacted at 160° C. for 5 hours whiledistilling water off. The resultant was cooled to room temperature andextracted from ethyl ether. The extract was washed with water,concentrated under a reduced pressure, added with 20 ml of concentratedhydrochloric acid and heated under reflux for an hour. The reactionsolution was cooled to room temperature, washed with ethyl ether andneutralized with aqueous NaOH solution. After extracting the resultantwith ethyl ether, the extract was dried over anhydrous sodium sulfateand concentrated under a reduced pressure, to give 16.9 g of the titlecompound.

Step 2: Preparation ofN-(Ethoxycarbonylmethyl)-1-(2'-Methylphenyl)Ethylamine

16.8 g of the compound(0.124M) prepared in Step 1 above, 17.3 ml oftriethylamine and 100 ml of tetrahydro-furan were mixed and 13.8 ml ofethyl bromoacetate(0.124M) was dropwise added thereto, followed byheating under reflux for an hour. The resultant was stirred at roomtemperature for 12 hours and added with ethyl ether. After filtering thesolids produced, the filtrate was washed with water, dried overanhydrous sodium sulfate and concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography, to give 23.3 gof the title compound.

Step 3: Preparation of N-(2-Hydroxyethyl)-1-(2-Methyl-Phenyl)Ethylamine

To a mixture of 3.8 g of lithium aluminium hydride (0.1M) and 150 ml oftetrahydrofuran, 23.3 g of the compound (0.105M) prepared in Step 2above was dropwise added at room temperature and stirred for 30 minutes.The resultant was added with water and solids produced were filtered.The filtrate was dried over anhydrous sodium sulfate and concentratedunder a reduced pressure, to give 13.8 g of the title compound.

Step 4: Preparation of N-(2-Bromoethyl)-1-(2'-Methyl-Phenyl)EthylamineHydrochloride

77 ml of 48% HBr was cooled to 0° C. and dropwise added at 0° C. to 13.8g of the compound(77 mM) prepared in Step 3 above. Then, 50 ml of thereaction solution was distilled off and the residue was cooled to roomtemperature. The solids obtained were recrystallized in a mixed solventof ethanol and ethyl ether to produce 14.75 g of the title compound.

Step 5: Preparation of 1,8-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

To a mixed solution of 14.7 g of the compound (45.5 mM) prepared in Step4 above and 100 ml of decaline, was added aluminium chloride and reactedat 140°-150° C. for 1.5 hours, which was cooled to 0° C. The reactionmixture was diluted by pouring into ice water and washed with ethylether. The reaction mixture was basified by adding aqueous NaOH solutionand the solids produced were filtered. The filtrate was extracted fromethyl ether and the extracts was dried over anhydrous sodium sulfate,concentrated under a reduced pressure, to give 3.16 g of the titlecompound.

Preparation 1-12: 1,6-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-11, exceptthat 13.41 g of 4-methylaceto-phenone(0.2M) was used as a startingmaterial, 2.8 g of the title compound was prepared.

Preparation 1-13: 1,4-Dimethyl-1,2,3,4-Tetrahydroisoquinoline

In accordance with the same procedures as in Preparation 1-1, exceptthat 14.5 ml of β-methylphenethyl-amine(0.1M) and 7.8 ml of acetylchloride(0.11M) were used as starting materials, 6.6 g of the titlecompound was prepared.

Preparation 2: Preparation of Substituted 2,4-Dichloro-Quinazolines ofFormula(II): Preparation 2-1: 2,4-Dichloroquinazoline

Step 1: Preparation of 2,4-Dihydroxyquinazoline

To a mixture containing 41 g of 2-aminobenzoic acid (0.3M), 21 of waterand 34 ml of acetic acid, was dropwise added 54 g of potassium cyanatedissolved in 200 ml of water. The resultant was stirred for an hour andslowly added with 60 g of 0.3M aqueous sodium hydroxide so as not toexceed the reaction temperature of 40° C. The solution, while heated to90° C., was stirred for 30 minutes, and then cooled to 0° C. Theresultant was acidified by adding a concentrated hydrochloric acid andthe solids thus produced were filtered to obtain 43.7 g of the titlecompound.

Step 2: Preparation of 2,4-Dichloroquinazoline

To 81 g of the compound(0.5M) prepared in Step 1 above, 200 ml ofphosphorous oxychloride and 28 ml of dimethylaniline were added; and theresultant was heated under reflux for 5 hours. The reaction mixture wasconcentrated under a reduced pressure, to give 40.2 g of the titlecompound as pale yellow solids.

Preparation 2-2: 8-Methoxy-2,4-Dichloroquinazoline

In accordance with the same procedures as in Preparation 2-1, exceptthat 57 g of 2-amino-3-methoxy-benzoic acid(0.43M) was used as astarting material 36 g of the title compound was obtained.

2-Chloro-4-(substituted-1,2,3,4-tetrahydroisoquinoline-2-yl)quinazolinesof formula(IV) are prepared in Examples 1-17

Example 1: Preparation of2-Chloro-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl) Quinazoline

10 g Of the compound(50.2 mM) prepared in Preparation 2-1, 70 ml ofdichloromethane and 7.8 ml of triethylamine (56 mM) were mixed and 6.4ml of 1,2,3,4-tetrahydroisoquinoline(50.2 mM) was dropwise added slowlywhile maintaining the reaction temperature below 10° C., which wasstirred at room temperature for 2 hours. The reaction mixture was driedover anhydrous sodium sulfate and concentrated under a reduced pressure.The residue was crystallized to give 14.6 g of the title compound.

Example 2: Preparation of2-Chloro-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 10 gof the compound(50.2 mM) prepared in Preparation 2-1 and 7.4 ml of thecompound(50.2 mM) prepared in Preparation 1-1 were used as startingmaterials, 13.5 g of the title compound was prepared.

Example 3: Preparation of2-Chloro-4-(1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 2.31g of the compound(11.6 mM) prepared in Preparation 2-1 and 1.85 g of thecompound(11.6 mM) prepared in Preparation 1-4 were used as startingmaterials, 3.0 g of the title compound was prepared.

Example 4: Preparation of2-Chloro-8-Methoxy-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 11.2g of the compound(48.8 mM) prepared in Preparation 2-2 and 6.2 ml of1,2,3,4-tetrahydroisoquinoline(48.8 mM) were used as starting materials,14.2 g of the title compound was prepared.

Example 5: Preparation of2-Chloro-8-Methoxy-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.35g of the compound(14.6 mM) prepared in Preparation 2-2 and 2.15 g of thecompound(14.6 mM) prepared in Preparation 1-1 were used as startingmaterials, 3.5 g of the title compound was prepared.

Example 6: Preparation of(R)-2-Chloro-8-Methoxy-4-(1-methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.0g of the compound(15.1 mM) prepared in Preparation 2-2 and 2.22 g of thecompound(15.1 mM) prepared in Preparation 1-2 were used as startingmaterials, 3.64 g of the title compound was prepared.

Example 7: Preparation of(S)-2-Chloro-8-Methoxy-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.0g of the compound(15.1 mM) prepared in Preparation 2-2 and 2.22 g of thecompound(15.1 mM) prepared in Preparation 1-3 were used as startingmaterials, 3.5 g of the title compound was prepared.

Example 8: Preparation of2-Chloro-8-Methoxy-4-(1-Trifluoromethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

To a mixture of 3.05 g of the compound(13.3 mM) prepared in Preparation2-2 and 20 ml of dimethylformamide, 2.68 g of the compound(13.3 mM)prepared in Preparation 1-5 was added and reacted at 110° C. for anhour. The reaction mixture was cooled, diluted with dichloromethane,washed with water, dried over anhydrous sodium sulfate and concentratedunder a reduced pressure. The residue produced was purified by columnchromatography to give 2.1 g of the title compound.

Example 9: Preparation of 2-Chloro-8-Methoxy-4-(1-Fluoromethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl ) Quinazoline

In accordance with the same procedures as in Example 1, except that 5.0g of the compound(22 mM) prepared in Preparation 2-2 and 4 g of thecompound(24 mM) prepared in Preparation 1-6 were used as startingmaterials, 6.8 g of the title compound was prepared.

Example 10: Preparation of2-Chloro-8-Methoxy-4-(1-Ethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.5g of the compound(15.3 mM) prepared in Preparation 2-2 and 2.46 g of thecompound(15.3 mM) prepared in Preparation 1-7 were used as startingmaterials, 4.07 g of the title compound was prepared.

Example 11: Preparation of2-Chloro-8-Methoxy-4-(1-Cyclopropyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 1.44g of the compound(6.30 mM) prepared in Preparation 2-2 and 1.15 g of thecompound(6.9 mM) prepared in Preparation 1-8 were used as startingmaterials, 2.25 g of the title compound was prepared.

Example 12: Preparation of2-Chloro-8-Methoxy-4-(3-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 5.0g of the compound(21.mM) prepared in Preparation 2-2 and 3.3 g of thecompound(22.4 mM) prepared in Preparation 1-9 were used as startingmaterials, 2.0 g of the title compound was prepared.

Example 13: Preparation of2-Chloro-8-Methoxy-4-(1,1-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 7.70g of the compound(34 mM) prepared in Preparation 2-2 and 6.50 g of thecompound(40 mM) prepared in Preparation 1-10 were used as startingmaterials, 4.9 g of the title compound was prepared.

Example 14: Preparation of2-Chloro-8-Methoxy-4-(1,8-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.6g of the compound(16 mM) prepared in Preparation 2-2 and 3.10 g of thecompound(19 mM) prepared in Preparation 1-11 were used as startingmaterials, 5.2 g of the title compound was prepared.

Example 15: Preparation of2-Chloro-8-Methoxy-4-(1,6-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 3.6g of the compound(16 mM) prepared in Preparation 2-2 and 2.80 g of thecompound(19 mM) prepared in Preparation 1-12 were used as startingmaterials, 5.2 g of the title compound was prepared.

Example 16: Preparation of2-Chloro-8-Methoxy-4-(1,4-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 4.65g of the compound(20 mM) prepared in Preparation 2-2 and 3.60 g of thecompound(22 mM) prepared in Preparation 1-13 were used as startingmaterials, 4.5 g of the title compound was prepared.

Example 17: Preparation of2-Chloro-8-Methoxy-4-(1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

In accordance with the same procedures as in Example 1, except that 2.64g of the compound(11.6 mM) prepared in Preparation 2-2 and 1.85 g of thecompound(11.6 mM) prepared in Preparation 1-4 were used as startingmaterials, 3.5 g of the title compound was prepared.

The quinazoline derivatives of formula(I) and pharmaceuticallyacceptable salts thereof are prepared in Examples 18-61.

Example 18: Preparation of2-(Phenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

To a mixture of 2.0 g of the compound(6.8mM) prepared in Example 1 and15 ml of dimethylformamide, 1.25 ml of aniline(13.6 mM) was added andreacted at 110°-120° C. for 2 hours. The resultant was cooled to roomtemperature, neutralized by adding aqueous NaOH solution and extractedfrom 50 ml of dichloromethane.

The extract was dried over anhydrous sodium sulfate and concentratedunder a reduced pressure. The residue produced was purified by silicagel column chromatography. The white solids produced were dissolved in100 ml of ethyl ether, added with ethyl ether solution saturated withhydrochloride. The solids thus obtained were filtered and dried undervacuum to give 0.6 g of the title compound.

Yield: 23%

M.P: 246°-248° C.

¹ H-NMR(DMSO-d₆):δ 3.1(bs, 2H), 4.18(bs, 2H), 5.16(s, 2H), 7.14-7.34(m,5H),7.47(t, 3H), 7.62(t, 3H), 7.86(t, 1H), 8.22(d, 1H) 10.64(s, 1H)

Example 19: Preparation of2-(N-Methylphenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 0.9 g of the compound(3 mM) prepared in Example 1 and 15 mlof dimethylformamide, 0.4 ml of N-methylaniline(3.6 mM) was added, 0.51g of the title compound was prepared.

Yield: 42%

M.P.: 206°-208° C.

¹ H-NMR(CDCI₃): δ 2.90(t, 2H), 3.91(t, 2H), 4.00(s, 3H), 4.82(s, 2H),6.98(d, 1H), 7.14-7.54(m, 9H), 7.75(t, 1H), 7.86(d, 1H),8.96(d, 1H),13.8(s, 1H)

Example 20: Preparation of2-(4-Fluoro-N-Methylphenyl-Amino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.2 g of the compound 7 mM prepared in Example 1 and 15 mlof dimethylformamide, 1.9 g of 4-fluoro-N-methylaniline(15 mM) wasadded, 2.45 g of the title compound was prepared.

Yield: 81%

M.P.: 242°-244° C.

¹ H-NMR(DMSO-d₆): δ 2.96(t, 2H), 3.71(s, 3H), 4.01(t, 2H), 5.03(s, 2H),7.23 (m, 4H), 7.25-7.62(m, 5H), 7.84(t, 1H), 8.20(t, 2H), 12.70 (bd, 1H)

Example 21: Preparation of2-(2-Methylphenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.05 g of the compound (10.3 mM) prepared in Example 1 and15 ml of dimethylform-amide, 2.2 ml of 2-methylaniline(20.6 mM) wasadded, 0.9 g of the title compound was prepared.

Yield: 22%

M.P.: 206°-209° C.

¹ H-NMR(DMSO-d₆): δ 2.35(s, 3H),3.30(bs, 2H),4.17(bs, 2H),5.17(s,2H),7.1-7.8(m, 10H), 7.9(t, 1H), 8.3(t, 1H), 10.1(s, 1H)

Example 22: Preparation of 2-(4-Fluoro-2-Methylphenyl-Amino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.2 g of the compound(7 mM) prepared in Example 1 and 15 mlof dimethylformamide, 1.7 ml of 4-fluoro-2-methylaniline(15 mM) wasadded, 1.35 g of the title compound was prepared.

Yield: 46%

M.P.: 210°-212° C.

¹ HNR(DMSO-d₆ +TFA-d): δ 2.33(s, 3H), 3.02(t, 2H), 4.10(t, 2H), 5.09(s,2H), 7.25(m, 6H), 7.47(t, 1H), 7.58(m, 2H), 7.86(t, 1H), 8.20(d, 1H),10.10(s, 1H), 13.25(bd, 1H)

Example 23: Preparation of2-(4-Fluorophenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.0 g of the compound. (10.1 mM) prepared in Example 1 and20 ml of dimethylform-amide, 1.9 ml of 4-fluoroaniline(20.2 mM) wasadded, 1.05 g of the title compound was prepared.

Yield: 26%

M.P.: 269°-271° C.

¹ H-NMR(DMSO-d₆): δ 3.06(t, 2H),4.15(t, 2H),5.14(s, 2H),7.16-7.40(m,6H), 7.46(t, 1H), 7.63(m, 3H), 7.85(t, 1H), 8.21(d, 1H),10.70(s, 1H)

Example 24: Preparation of2-(N-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.4 g of the compound (4.52 mM) prepared in Example 2 and15 ml of dimethyl-formamide, 1.1 ml of N-methylaniline(10.1 mM) wasadded, 1.02 g of the title compound was prepared.

Yield: 54%

M.P.: 213°-215° C.

¹ H-NMR(DMSO-d₆): δ 1.23-1.64(m, 2H), 2.69-3.30(m, 2H), 3.44-3.75(m,1H), 3.98(s, 3H), 4.26-4.47(m, 1H), 5.23-5.40(m, 1H), 7.17-7.56 (m,2H),7.70-7.83(m, 9H), 8.94(d, 1H), 13.88(s, 1H)

Example 25: Preparation of2-(4-Fluorophenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.26 g of the compound (4.07 mM) prepared in Example 2 and15 ml of dimethylform-amide, 0.81 ml of 4-fluoroaniline(8.54 mM) wasadded, 1.59 g of the title compound was prepared.

Yield: 93%

M.P.: 250°-252° C.

¹ H-NMR(CDCl₃): δ 1.68-1.87(m, 3H), 2.96-3.42(m, 2H), 3.74-3.88(m, 1H),4.64-4.72(m, 1H), 5.67-5.73(m, 1H), 7.03-7.96(m, 12H), 10.65(s, 1H),13.84(s, 1H)

Example 26: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 14, except that toa mixture of 1.61 g of the compound (5.20 mM) prepared in Example 2 and15 ml of dimethyl-formamide, 0.89 ml of 4-fluoro-2-methylaniline(10.9mM) was added, 1.76 g of the title compound was prepared.

Yield: 78%

M.P.: 260°-263° C.

¹ H-NMR(CDCl₃): δ 1.54-1.82(m, 3H), 2.43(s, 3H), 2.85-3.38(m, 2H),3.61-3.37 (m, 1H), 4.52-4.65(m, 1H), 5.60(q, 1H), 6.90-7.07(m, 3H),7.17-7.27(m, 3H), 7.34-7.50(m, 2H), 7.67-7.78(m, 2H), 7.89(d,1H),10.02(s, 1H), 14.18(s, 1H)

Example 27: Preparation of 2-(4-Fluoro-2-Methylphenyl-Amino)-4-(1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline-2-Yl) QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.50 g of the compound (4.46 mM) prepared in Example 3 and15 ml of dimethylform-amide, 0.80 ml of 4-fluoro-2-methylaniline(9.79mM) was added, 1.64 g of the title compound was prepared.

Yield: 79%

M.P.: 248°-250° C.

¹ H-NMR(CDCl₃): δ 1.55-1.78(m, 1H,), 2.33(s, 3H), 2.53-2.99(m, 4H),3.82-4.02(m,1H), 4.37-4.50(m, 1H), 5.02-5.30(m, 1H), 6.60-7.01 (m, 5H),7.43(t, 1H), 7.59-7.67(m, 2H), 7.86(t, 1H), 8.14(d, 1H), 10.13(s, 1H),13.40(s, 1H)

Example 28: Preparation of8-Methoxy-2-(phenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.5 g of the compound (4.6 mM) prepared in Example 4 and 15ml of dimethylform-amide, 0.65 ml of aniline(6.9 mM) was added, 1.40 gof the title compound was prepared.

Yield: 73%

M.P.: 181°-183° C.

¹ H-NMR(DMSO-d₆): δ 3.14(t,2H),4.06(s, 3H),4.23(t, 2H),5.14(s,2H),7.05-7.40 (m, 9H), 7.50(d, 1H), 7.74(d, 2H), 11.90(s, 1H), 12.89(s,1H)

Example 29: Preparation of8-Methoxy-2-(N-Methylphenyl-Amino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.0 g of the compound. (6.14 mM) prepared in Example 4 and15 ml of dimethylform-amide, 1.46 ml of N-methylaniline(12.28 mM) wasadded, 1.5 g of the title compound was prepared.

Yield: 56%

M.P.: 90°-92° C.

H-NMR(DMSO-d₆): δ 3.12(t, 2H), 3.83(s, 3H), 3.96(s, 3H), 4.24(t, 2H),5.15(s, 2 H),7.10-7.26(m, 5H), 7.28-7.72(m, 7H)

Example 30: Preparation of8-Methoxy-2-(4-Fluorophenyl-Amino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.5 g of the compound (4.6 mM) prepared in Example 4 and 15ml of dimethyl-formamide, 0.85 ml of 4-fluoroaniline(9.2 mM) was added,1.3 g of the title compound was prepared.

Yield: 65%

M.P.: 239°-241° C.

¹ H-NMR(DMSO-d₆): δ 3.12(t, 2H), 4.07(s, 3H), 4.20(t, 2H), 5.12(s, 2H),6.98-7.49 (m, 3H), 7.40-7.68(m, 8H), 11.80(bs, 1H)

Example 31: Preparation of 8-Methoxy-2-(4-Fluoro-2-Methyl-Phenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-yl) QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.26 g of the compound (10 mM) prepared in Example 4 and 15ml of dimethyl-formamide, 1.7 ml of 4-fluoro-2-methylaniline(20 mM) wasadded, 2.5 g of the title compound was prepared.

Yield: 55%

M.P.: 195-197° C.

¹ H-NMR(DMSO-d₆): δ 2.42(s, 3H), 3.01(t, 2H), 4.09(t, 2H), 4.10(s, 3H),5.00(s, 2H), 6.80-7.56(m, 11H), 11.20(s, 1H)

Example 32: Preparation of8-Methoxy-2-(4-Fluoro-N-Methyl-Phenylamino)-4-(1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.0 g of the compound (6.14 mM) prepared in Example 4 and15 ml of dimethyl-formamide, 1.5 g of 4-fluoro-N-methylaniline(12.2 mM)was added, 1.05 g of the title compound was prepared.

Yield: 38%

M.P.: 93°-95° C.

¹ H-NMR(DMSO-d₆): δ 3.08(t, 2H), 3.88(s, 3H), 4.01(s, 3H), 4.16(t, 2H),5.06(bs, 2H), 7.08-7.60(m, 1H)

Example 33: Preparation of8-Methoxy-2-(4-Fluorophenyl-Amino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.50 g of the compound (4.41 mM) prepared in Example 5 and15 ml of dimethyl-formamide, 0.88 ml of 4-fluoroaniline(9.27 mM) wasadded, 0.97 g of the title compound was prepared.

Yield: 49%

M.P.: 155°-157° C.

¹ H-NMR(CDCI₃): δ 1.58-1.98(m, 3H), 2.85-3.46(m, 2H), 3.73-3.97(m, 1H),4.07(s, 3H), 4.64-4.77(m, 1H), 5.73(q, 1H), 7.03-7.67(m, 11H), 11.85(s,1H), 12.82(s, 1H)

Example 34: Preparation of8-Methoxy-2-(4-Fluoro-2-Methyl-Phenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 8, except that to amixture of 1.50 g of the compound (4.41 mM) prepared in Example 5 and 15ml of dimethyl-formamide, 0.75 ml of 4-fluoro-2-methylaniline(9.27 mM)was added, 0.78 g of the title compound was prepared.

Yield: 38%

M.P.: 231°-233° C.

¹ H-NMR(CDCl₃): δ 1.51-1.90(m, 3H), 2.42(s, 3H), 2.84-3.35(m, 2H),3.57-3.81 (m, 1H), 4.10(s, 3H, 4.51-4.66(m, 1H), 5.58(q, 1H), 6.89-7.44(m, 11H), 11.12(s, 1H, 13.16(s, 1H)

Example 35: Preparation of(R)-8-Methoxy-2-(4-Fluoro-2-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.64 g of the compound (7.77 mM) prepared in Example 6 and15 ml of dimethyl-formamide, 1.33 ml of 4-fluoro-2-methylaniline(16.3mM) was added, 1.50 g of the title compound was prepared.

Yield: 42%

M.P.: 230°-233° C.

¹ H-NMR(CDCl₃): δ 1.51-1.90(m, 3H), 2.42(s, 3H), 2.84-3.35(m, 2H),3.57-3.81 (m, 1H), 4.10(s, 3H), 4.51-4.66(m, 1H), 5.58(q, 1H), 6.89-7.44(m, 11H), 11.12(s, 1H), 13.16(s, 1H)

Example 36: Preparation of(S)-8-Methoxy-2-(4Fluoro-2-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.64 g of the compound (7.77 mM) prepared in Example 7 and15 ml of dimethyl-formamide, 1.33 ml of 4-fluoro-2-methylaniline(16.3mM) was added, 1.60 g of the title compound was prepared.

Yield: 44%

M.P.: 230°-232° C.

¹ H-NMR(CDCl₃): δ 1.51-1.90(m, 3H), 2.42(s, 3H), 2.84-3.35(m, 2H),3.57-3.81 (m, 1H), 4.10(s, 3H), 4.51-4.66(m, 1H), 5.58(q, 1H), 6.89-7.44(m, 11H), 11.12(s, 1H), 13.16(s, 1H)

Example 37: Preparation of8-(2-Hydroxyethyloxy)-2-(4-Fluoro-2-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

Step 1: Preparation of8-Hydroxy-2-(4-Fluoro-2-Methyl-Phenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

To a mixture of 4.1 g of the compound(9.6 mM) prepared in Example 34 and50 ml of dichloromethane, 48 ml of tribromoboran was added at 0° C. Theresultant was stirred at room temperature for 14 hours and then pouredinto ice water. The solids produced were filtered, dissolved indichloromethane, and neutralized by adding aqueous NaOH solution. Thedichloromethane layer was separated, dried over anhydrous sodium sulfateand concentrated to give 2.4 g of the title compound.

Yield: 60%

¹ H-NMR(DMSO-d₆): δ 1.48(m, 3H), 2.07(s, 3H), 2.59(t, 1H), 3.00(m, 1H),3.42(t, 1H), 5.58(q, 1H), 6.80-7.20(m, 9H), 7.40(d, 1H), 9.40(s, 1H),11.40(s, 1H)

Step 2: Preparation of8-(Ethoxycarbonylmethyloxy)-2-(4-Fluoro-2-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

To a mixture of 0.2 g of 65% sodium hydride(5.8 mM) and 15 ml ofdimethylformamide, 2.4 g of the compound(5.8 mM) prepared in Step 1above was dropwise added at 0° C., followed by stirring 30 minutes.Then, 0.65 ml of ethylbromo acetate(5.8 mM) was dropwise added theretoand stirred for an hour. The resultant was added with water andneutralized by adding sodium bicarbonate. After extracting the resultantfrom dichloromethane, the dichloromethane layer was dehydrated andconcentrated. The residue was purified by dried silica gel columnchromatography using ethyl acetate:hexane(1:2), to give 2.0 g of thetitle compound.

Yield: 70%.

¹ H-NMR(DMSO-d₆): δ 1.30(t, 3H), 1.48(m, 3H), 2.07(s, 3H), 2.59(t, 1H),3.00(m, 1H), 3.42(t, 1H), 4.30(q, 2H), 4.85(s, 2H), 5.58(q, 1H),6.80-7.20(m, 9H), 7.40(d, 1H), 9.40(s, 1H),

Step 3: Preparation of8-(2-Hydroxyethyloxy)-2-(4-Fluoro-2-Methylphenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline

To a mixture of 0.12 g of lithium aluminium hydride (3.0 mM) and 30 mlof tetrahydrofuran, 1.5 g of the compound (3.0 mM) prepared in Step 2dissolved in tetrahyrofuran was dropwise added at 0° C. and stirred foran hour. The reaction solution was added with water and extracted fromdichloromethane. The dichloromethane layer was dehydrated, concentratedand purified by silica gel column chromatography, to give 0.80 g of thetitle compound.

Yield: 58%

M.P.: 120°-122° C.

¹ H-NMR(DMSO-d₆): δ 1.48(m, 3H), 2.07(s, 3H), 2.59(t, 1H), 3.00(m, 1H),3.42(t, 1H), 3.90-4.20(m, 4H), 5.58(q, 1H), 6.80-7.20(m, 9H), 7.40(d,1H), 9.40(s, 1H)

Example 38: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Ethoxy-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

To a mixture of 0.2 g of 65% sodium hydride(5.8 mM) and 15 ml ofdimethylformamide, 2.0 g of the compound (4.8 mM) prepared in Step 1 ofExample 37 was dropwise added at 0° C., followed by stirring 30 minutes.Then, a mixture of 0.4 ml of iodoethane(4.8 mM) and 5 ml ofdimethylformamide was dropwise added thereto and stirred at roomtemperature for 2 hours. The resultant was added with water andneutralized by adding sodium bicarbonate. After extracting the resultantfrom ethyl acetate, the ethyl acetate layer was dehydrated andconcentrated. The residue was purified by silica gel columnchromatography, and dissolved in ethyl ether; and hydrochloric acid wasadded thereto. The solid produced were filtered and dried under vaccum,to give 0.52 g of the title compound.

Yield: 22%

M.P.: 165°-170° C.

1H-NMR(CDCl3) :δ 1.54-1.76(m, 6H), 2.40(s, 3H), 2.80-3.32(m, 2H),3.54-3.80 (m, 1H), 4.28(q, 2H), 4.48-4.62(m, 1H), 5.52(q, 1H),6.92-7.04(m, 3H), 7.15-7.41(m, 7H), 11.22(s, 1H), 13.00(s, 1H)

Example 39: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino-8-(Methylthiomethyloxy)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 38, except that 0.2g of 65% of sodium hydride(5.8 mM), 2.0 g of the compound(4.8 mM)prepared in Step 1 of Example 37 and 0.4 ml methylthiomethylchloride(4.8mM) were used as starting materials, 0.52 g of the title compound wasprepared.

Yield: 7.1%

M.P.: 94°-96° C.

1H-NMR(CDCl3) :δ 1.65-1.76(d, 3H), 2.32(s, 6H), 2.76(d, 1H), 3.30(m,1H), 3.60 (t, 1H), 4.38(m, 1H), 5.42(m, 3H), 6.68(s, 1H), 6.90(d, 2H),7.00-7.20(m, 5H), 7.50(d, 1H), 7.92(m, 1H)

Example 40: Preparation of8-Methoxy-2-(N-Methylphenyl-Amino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 8.00 g of the compound (8.82 mM) prepared in Example 5 and15 ml of dimethyl-formamide, 2.00 ml of N-methyl aniline(18.45 mM) wasadded, 0.85 g of the title compound was prepared.

Yield: 22%

M.P.: 93°-95° C.

¹ H-NMR(CDCl₃) :δ 1.63(bs, 3H), 2.80 -3.36(m, 2H), 3.50-4.00(m, 1H),4.47-4.57(m, 1H), 5.59-5.69(m, 1H), 7.21-7.68(m, 12H), 10.44(s, 1H)

Example 41: Preparation of 8-Methoxy-2-(4-Fluoro-N-methyl-Phenylamino)-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.00 g of the compound (2.94 mM) prepared in Example 5 and15 ml of dimethyl-formamide, 0.77 g of 4-fluoro-N-methyl aniline(6.18mM) was added, 0.66 g of the title compound was prepared.

Yield: 44%

M.P.: 100°-103° C.

¹ H-NMR(CDCl₃): δ 1.58-1.82(m, 1H), 2.82-3.61(m, 2H), 3.67-4.05(m, 1H),4.51-4.64(m, 1H), 5.51-5.63(m, 1H), 7.00-7.13(m, 1 H), 9.80(bs, 1H)

Example 42: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1-Trifluoromethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.9 g of the compound (4.82 mM) prepared in Example 8 and15 ml of dimethyl-formamide, 0.82 ml of 4-fluoro-2-methyl aniline(10.1mM) was added, 1.32 g of the title compound was prepared.

Yield: 53%

M.P.: 158°-160° C.

1H-NMR(CDCl3) :δ 2.38(s, 3H), 2.97-3.30(m, 2H), 3.98-4.18(m, 4H),4.65-4.82 (m, 1H), 6.301(q, 1H), 6.85-7.00(m, 2H), 7.15-7.38(m, 7H),7.50(d, 1H), 11.40(s, 1H), 14.40(s, 1H), 14.55(s, 1H)

Example 43: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(1-Fluoromethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.3 g of the compound (9 mM) prepared in Example 9 and 15ml of dimethylform-amide, 1.9 ml of 4-fluoroaniline(20.0 mM) was added,0.61 g of the title compound was prepared.

Yield: 14.5%

M.P..: 208°-211° C.

1H-NMR(CDCl3) :δ 3.02(bd, 1H), 3.25(m, 1H), 3.94(bd, 1H), 4.06(s, 3H),4.74(d, 2H), 5.00(m, 1H), 6.02(tt, 1H), 7.08(t, 2H), 7.20(m, 6H),7.58(m, 3H), 11.90(s, 1H), 12.96(s, 1H)

Example 44: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1-Fluoromethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.3 g of the compound (9.0 mM) prepared in Example 9 and 15ml of dimethylform-amide, 2.2 ml of 4-fluoro-2-methylaniline(20 mM) wasadded, 0.65 g of the title compound was prepared.

Yield: 15%

M.P.: 122°-130° C.

1H-NMR(CDCl3) :δ 2.40(s, 3H), 2.84-2.95(bd, 2H), 3.15(bd, 1H), 4.86(bd,1H), 4.10(s, 3H), 4.62(bd, 1H), 4.64-4.88(dd, 2H), 5.80(tt, 1H),6.90-7.08(m, 3H), 7.19-7.40(m, 6H), 7.62(d, 1H)

Example 45: Preparation of8-Methoxy-2-(4-Fluorophenyl-Amino)-4-(1-Ethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.50 g of the compound (4.63 mM) prepared in Example 10 and15 ml of dimethyl-formamide, 0.65 ml of 4-fluoroaniline(6.95 mM) wasadded, 1.20 g of the title compound was prepared.

Yield: 56%

M.P.: 187°-189° C.

¹ H-NMR(DMSO-d₆): δ 0.82(t, 3H), 1.90(bs, 1H), 2.08(m, 1H), 3.10(m,3H),4.02(s, 3H), 4.15(bs, 1H), 4.51(m, 1H), 5.70(t, 1H), 7.20-7.80(m, 11H),11.20(s, 1H), 12.05(s, 1H)

Example 46: Preparation of8-Methoxy-2-(2-Methyl-4-Fluoro-Phenylamino)-4-(1-Ethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.5 g of the compound (4.63 mM) prepared in Example 10 and15 ml of dimethyl-formamide, 0.80 ml of 2-methyl-4-fluoroaniline(9.73mM) was added, 0.70 g of the title compound was prepared.

Yield: 32%

M.P.: 145°-147° C.

¹ H-NMR(DMSO-d₆): δ 0.66(t, 3H), 1.72(bs, 1H), 1.94(m, 1H), 2.32(s, 3H),3.06 (m, 3H), 3.96-4.20(bs+s, 4H), 4.40(m, 1H), 5.45(t, 1H),7.00-7.80(m, 10H), 10.58(bs, 1H), 12.42(bs, 1H)

Example 47: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1-cyclopropyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.25 g of the compound (6.15 mM) prepared in Example 11 and15 ml of dimethyl-formamide, 1.05 ml of 4-fluoro-2-methylaniline(12.9mM) was added, 2.15 g of the title compound was prepared.

Yield: 71%

M.P.: 134°-136° C.

1H-NMR(CDCl3) :δ 0.10-0.50(m, 3H), 0.52-0.66(m, 1H), 1.16-1.36(m, 1H),2.39 (s, 1H), 3.00-3.40(m, 2H), 4.08-4.25(m, 4H), 4.50-4.70(m, 1H),5.36(d, 1H), 6.87-7.05(m, 3H), 7.16-7.36(m, 6H), 7.48 (d, 1H), 11.10(d,1H), 13.04(s, 1H)

Example 48: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(3-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.5 g of the compound (4.4 mM) prepared in Example 12 and15 ml of dimethyl-formamide, 0.7 ml of 4-fluoroaniline(6.6 mM) wasadded, 0.7 g of the title compound was prepared.

Yield: 35%

M.P.: 150°-153 C.

¹ H-NMR(CDCl3) :δ 1.38(d, 3H), 2.80(d, 1H), 3.37(d, 1H), 4.08 (s, 3H),4.92(d, 1H), 5.30(m, 2H), 6.90-7.40(m, 8H), 7.40-7.70(m, 3H), 11.90(s,1H), 12.80(s, 1H)

Example 49: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(3-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.0 g of the compound (5.9 mM) prepared in Example 12 and15 ml of dimethyl-formamide, 1.1 ml of 4-fluoro-2-methylaniline(8.9 mM)was added, 0.8 g of the title compound was prepared.

Yield: 29%

M.P.: 214°-217° C.

1H-NMR(CDCl3) :δ 1.30(d, 3H), 2.40(s, 3H), 2.70(d, 1H), 3.22 (d, 1H),4.10(s, 3H), 4.86(m, 1H), 5.10-5.30(m, 2H), 6.90-7.50(m, 10H), 11.20(s,1H), 13.20(s, 1H)

Example 50: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(1,1-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.80 g of the compound (5.0 mM) prepared in Example 13 and10 ml of dimethyl-formamide, 1.10 ml of 4-fluoroaniline(11 mM) wasadded, 1.14 g of the title compound was prepared.

Yield: 49%

M.P.: 134°-138° C.

1H-NMR(CDCl3) :δ 1.75(s, 6H), 3.22(t, 2H), 4.00(t, 2H), 4.09(s, 3H),7.13(m, 6H), 7.25(m, 2H),7.40(m, 3H), 11.62(s, 1H), 13.08(s, 1H)

Example 51: Preparation of2-(4-Fluoro-2-Methylphenyl-1-Amino)-8-Methoxy-4-(1,1-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.80 g of the compound (5.0 mM) prepared in Example 13 and10 ml of dimethyl-formamide, 1.20 ml of 4-fluoro-2-methylaniline(11 mM)was added, 0.81 g of the title compound was prepared.

Yield: 34%

M.P.: 176°-180° C.

1H-NMR(CDCl3) :δ 1.56(s, 6H), 2.36(s, 3H), 3.21(t, 2H), 3.98(t, 2H),4.11(s, 3H), 6.94(m, 2H), 7.16-7.38(m, 8H), 11.22(s, 1H), 13.40(s, 1H)

Example 52: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(1,8-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.3 g of the compound(9 mM) prepared in Example 14 and 15ml of dimethylformamide, 1.9 ml of 4-fluoroaniline(20 mM) was added,1.14 g of the title compound was prepared.

Yield: 49%

M.P.: 134°-138° C.

1H-NMR(CDCl3) :δ 1.74(s, 3H), 1.23(d, 3H), 2.82-3.37(m, 2H),3.68-3.84(m, 1H), 4.05(s, 3H),4.58-4.80(m, 1H), 5.66(q, 1H), 6.90-7.32(m, 7H), 7.45(d, 1H), 7.58-7.66(m, 2H), 11.20(s, 1H)

Example, 53: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1,8-dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.50 g of the compound (7.06 mM) prepared in Example 14 and15 ml of dimethyl-formamide, 1.21 ml of 4-fluoro-2-methylaniline(14.9mM) was added, 0.70 g of the title compound was prepared.

Yield: 21%

M.P.: 128°-131° C.

¹ H-NMR(CDCl3) :δ 1.56(s, 3H), 2.22(s, 3H), 2.31(s, 3H), 2.74-3.20(m,2H), 3.62-3.79(m, 1H), 3.98(s, 3H), 4.36-4.52(m, 1H), 5.50(q, 1H),6.80-7.25(m, 5H), 7.38-7.50(m, 2H), 7.53-7.77(m, 2H), 10.28(s, 1H),12.35(s, 1H)

Example 54: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(1,6-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.50 g of the compound (7.06 mM) prepared in Example 15 and10 ml of dimethyl-formamide, 1.40 ml of 4-fluoroaniline(4.8 mM) wasadded, 2.0 g of the title compound was prepared.

Yield: 61%

M.P.: 124°-128° C.

1H-NMR(CDCl3) :δ 1.73(bs, 3H), 2.32(s, 3H), 2.88-3.3 g(m, 2H),3.66-3.86(m, 1H), 4.07(s, 3H), 4.60-4.74(m, 1H), 5.70(q, 1H), 6.96-7.18(m, 6H), 7.31 (t, 1H), 7.45(d, 1H), 7.60-7.77(m, 2H), 11.80 (s, 1H),12.76(s, 1H)

Example 55: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1,6-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 2.50 g of the compound (7.06 mM) prepared in Example 15 and10 ml of dimethyl-formamide, 1.21 ml of 4-fluoro-2-methylaniline(14.9mM) was added, 1.10 g of the title compound was prepared.

Yield: 33%

M.P.: 130°-135° C.

1H-NMR(CDCl3) :δ 1.63(bs, 3H), 2.42(s, 3H), 2.70-3.30(m, 2H), 3.31(s,3H), 3.62-3.79(m, 1H), 3.50-3.85(m, 1H), 4.09(s, 3H), 4.50-4.62 (m, 1H),5.55(q, 1H), 6.80-7.22(m, 6H), 7.28(t, 1H), 7.37-7.46(m, 2H), 11.11(m,2H), 13.12(s, 1H)

Example 56: Preparation of2-(4-Fluorophenylamino)-8-Methoxy-4-(1,4-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.00 g of the compound (8.40 mM) prepared in Example 16 and10 ml of dimethyl-formamide, 1.90 ml of 4-fluoro-2-methylaniline(20 mM)was added, 1.10 g of the title compound was prepared.

Yield: 30%

M.P.: 145°-149° C.

1H-NMR(CDCl3) :δ 1.42(d, 3H), 1.83(bd, 3H), 3.24(bd, 2H), 4.08(s, 3H),4.60 (bd, 1H), 5.72(q, 1H), 6.84(t, 1H), 7.10(m, 2H), 7.30(m, 6H),7.63(m, 1H),11.80(s, 1H), 12.78(bd, 1H)

Example 57: Preparation of 2-(4-fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1,4-Dimethyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Hydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 3.10 g of the compound (8.76 mM) prepared in Example 16 and10 ml of dimethyl-formamide, 2.20 ml of 4-fluoro-2-methylaniline(20 mM)was added, 1.40 g of the title compound was prepared.

Yield: 34%

M.P.: 135°-139° C.

1H-NMR(CDCl3) :δ 1.12-1.37(bd, 3H), 2.40(s, 3H), 3.20(bd, 2H), 4.12(s,3H), 4.43(q, 1H), 5.57-5.7 6(qq, 1H), 6.95(m, 3H), 7.30(m, 5H), 7.42(m,2H), 10.82(bd, 1H)

Example 58: Preparation of8-Methoxy-2-(4-Fluorophenyl-Amino)-4-(1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.10 g of the compound (3.10 mM) prepared in Example 17 and15 ml of dimethyl-formamide, 0.5 ml of 4-fluoroaniline(4.6 mM) wasadded, 0.9 g of the title compound was prepared.

Yield: 63%

M.P.: 186°-196° C.

¹ -NMR(CDCl3): δ 1.78(m, 1H,), 2.70-3.05(m, 4H), 3.90(m, 1H), 4.06(s,3H), 4.48(d, 1H), 5.38(m, 1H), 7.09-7.40(m, 6H), 7.52(d, 1H), 7.70 (d,3H), 11,18(s, 1H), 12.10(bs, 1H),

Example 59: Preparation of8-Methoxy-2-(4-Fluoro-2-Methyl-Phenylamino)-4-(1,8-Ethano-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineHydrochloride

In accordance with the same procedures as in Example 18, except that toa mixture of 1.50 g of the compound (4.46m14) prepared in Example 17 and15 ml of dimethyl-formamide, 0.80 ml of 4-fluoro-2-methylaniline(9.79mM) was added, 1.64 g of the title compound was prepared.

Yield: 37%

M.P.: 195°-197° C.

¹ H-NMR(CDCl₃): δ 1.60(m, 1H,), 2.33(s, 3H), 2.42-2.93(m, 4H), 3.90(m,1H), 4.06(s, 3H), 4.48(m, 1H), 5.10(m, 1H), 7.10-7.80(m, 9H), 10.40(bs,1H), 12.40(bs, 1H)

Example 60: Preparation of2-(4-Fluoro-2-MethylPhenyl-Amino)-8-Methoxy-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)QuinazolineMethanesulfonate

To a mixture of 1.20 g of the compound(2.80 mM) prepared in Example 34and 50 ml of dichloromethane, 0.2 ml of methane sulfonate(3.08 mM) wasdropwise added. The resultant was stirred at room temperature for 30minutes and Concentrated under a reduced pressure. The residue producedwas crystallized by adding ethyl ether to give 1.32 g of the titlecompound.

Yield: 90%

M.P.: 109°-115° C.

1H-NMR(CDCl3) :δ 1.40-1.80(m, 3H), 2.35(s, 3H), 2.93-3.40(m, 5H),3.58-3.90 (m, 1H), 4.11(s, 3H), 4.48-4.63(m, 1H), 5.53(q, 1H),6.89-7.04(m, 3H), 7.17-7.25(m, 4H), 7.31-7.46(m, 3H), 10.08(s, 1H),12.43(s, 1H)

Example 61: Preparation of2-(4-Fluoro-2-Methylphenyl-Amino)-8-Methoxy-4-(1-Methyl-1,2,3,4-Tetrahydroisoquinoline-2-Yl)Quinazoline Malate

To a mixture of 0.27 g of maleic acid(2.33 mM) and 50 ml of ethanol,1.20 g of the compound (2.80 mM) prepared in Example 34 was dropwiseadded. The resultant was stirred at room temperature for 12 hours andconcentrated under a reduced pressure. The residue produced wascrystallized by adding ethyl ether and ethyl acetate, to give 1.15 g ofthe title compound.

Yield: 75%

M.P.: 190°-192° C.

1H-NMR(CDCl3) :δ 1.44-1.70(m, 3H), 2.32(s, 3H), 2.8-3.2 g(m, 2H),3.55-3.75 (m, 1H), 4.11(s, 3H), 4.43-4.60(m, 1H), 5.53(q, 1H), 6.35 (s,3H), 6.8-7.04(m, 3H), 7.17-7.35(m, 6H), 7.43(d, 1H), 12.00(s, 1H),13.10(s, 1H)

EXPERIMENT 1 Inhibition of Proton Pump(H⁺ /K⁺ ATPase) Activity

1-1: Preparation of a Proton Pump Enzyme Source

A New Zealand white rabbit was killed by blowing its head and thestomach was taken out. The contents of the stomach were removed and thestomach walls were washed with was saline. The inner wall of the stomachwas scratched out with a slide glass and the cells thus obtained werehomogenized in 0.25M sucrose buffer by means of a Teflon-glasshomogenizer. The homogenous solution was centrifuged at 10,000 g for 10minutes and the supernatant was further centrifuged at 20,000 g for 20minutes. The supernatant thus obtained was centrifuged at an ultra-highspeed of 180,000 g for 1 hour. The pellets precipitated were collectedby discarding the supernatant and suspended in 50 mM Tris-HCl bufferhaving pH 7.2. The suspension was dialyzed twice with the same buffer(of1,000 times volume) for 3 hours and stored into liquid nitrogen.

The above centrifugation and dialysis were carried out at 4° C. Themicrosomes thus obtained were used as an enzyme source of the in vitroenzyme reaction study of proton pump.

1-2: Measurement of Proton Pump Activity

The inhibitory effects of proton pump activity by the compounds of thepresent invention were measured by the in vitro enzyme reaction study.The proton pump activity stimulated by Mg⁺⁺ was used as a negativecomparative group, and the activity stimulated by Mg⁺⁺ and K⁺ was usedas a positive comparative group. The comparative compound wasomeprazole.

Test tubes were divided into 4 groups: Group 1 as negative comparativegroup(n=3), Group 2 as positive comparative group(n=3), Group 3(n=5) tobe administered with the compound of the present invention and Group4(n=5) to be administered with the comparative compound. The inhibitoryeffects of proton pump activity of Groups 3 and 4 were measured byemploying the compound prepared in Example 34 and omeprazole,respectively, each of which was dissolved in dimethylsulfoxide at 5different concentrations.

To each of Groups 1, 2, 3 and 4, were added 0.1 ml of magnesiumchloride(40 mM) dissolved in 50 mM Tris-HCl buffer (pH 7.2) and 50 Ng ofthe enzyme source prepared in Experiment 1-1. Then, 0.1 ml of potassiumchloride(500 mM) and 0.1 ml of ammonium chloride(100 mM) dissolved in 50mM Tris-HCl buffer(pH 7.2) were added to all groups except for Group 1.

0.1 ml of dimethylsulfoxide was added to each of Groups 1 and 2; and toGroup 3 was added 0.01 ml of the solution in which the compound preparedin Example 34 was dissolved in dimethylsulfoxide at 5 differentconcentrations. To Group 4, 0.01 ml of the solution prepared bydissolving omprazole in dimethylsulfoxide at 5 differentconcentrations(37.6, 21.4, 12.2, 7.0 and 4.0 μM) was added. 50 mMTris-HCl buffer was added thereto so as to make the total volume 0.4 ml.

Thereafter, the test tubes of each Group were placed at 37° C. for 15minutes for the prereaction. 0.1 ml of ATP solution(33.3 mM), which wasprepared by adding Tris-ATP 50 mM to Tris-HCl buffer having pH 7.2, wasadded until the reaction volume became 0.5 ml. The final concentrationsof MgCl₂, KCl, NH₄ Cl, ATP, enzyme and Tris-HCl were 8 mM, 100 mM, 20mM, 6.7 mM, 100μg/ml and 50 mM, respectively. After the reaction wascarried out at 37° C. for 30 minutes, 25% cold trichloroacetic acid wasadded to terminate the enzyme reaction. The released inorganic phosphatewas measured by an automatic analyzer(SBA 300, Gilford).

The difference between Group 1 and Group 2 represents the proton pumpactivity activated by K⁺ only. The inhibition percentages of Groups 3and 4 were calculated from Litchfield-wilcoxon equation see J.Pharmacol. Exptl. Ther. 96, 99(1949)!. The concentrations of the testcompounds which inhibit 50% of the proton pump activity are representedas IC₅₀ in Table 1.

                  TABLE 1                                                         ______________________________________                                        The Inhibition (50%) of the proton pump activity                                      IC.sub.50 of test                                                                           IC.sub.50 of                                                                              Effect                                      compound                                                                              compound (μM)                                                                            Omeprazole (μM)                                                                        ratio                                       ______________________________________                                        Example 18                                                                            0.6           37.0        61.67                                       Example 19                                                                            5.2           9.5         1.83                                        Example 20                                                                            8.4           9.2         1.10                                        Example 21                                                                            1.2           7.4         6.17                                        Example 22                                                                            0.7           7.9         11.29                                       Example 23                                                                            2.0           8.6         4.30                                        Example 24                                                                            ˜12.5   16.1        ˜1.29                                 Example 25                                                                            2.7           16.1        5.88                                        Example 26                                                                            0.4           16.1        46.00                                       Example 27                                                                            2.9           5.7         1.97                                        Example 28                                                                            1.2           8.3         6.92                                        Example 29                                                                            4.9           7.2         1.47                                        Example 30                                                                            2.2           7.2         3.27                                        Example 31                                                                            2.0           10.1        5.13                                        Example 32                                                                            >16.0         9.3         >0.58                                       Example 33                                                                            2.3           2.8         1.22                                        Example 34                                                                            1.7           9.2         5.45                                        Example 35                                                                            1.8           5.1         2.83                                        Example 36                                                                            4.0           5.1         1.28                                        Example 37                                                                            ˜12.5   7.5         ˜0.60                                 Example 38                                                                            1.2           2.0         1.67                                        Example 39                                                                            4.0           2.8         0.70                                        Example 40                                                                            1.3           10.6        8.15                                        Example 41                                                                            3.8           7.6         2.00                                        Example 42                                                                            12.5          2.2         <0.18                                       Example 43                                                                            >12.5         12.1        <0.97                                       Example 44                                                                            ˜12.5   12.1        ˜0.97                                 Example 45                                                                            8.9           4.1         0.46                                        Example 46                                                                            ˜6.0    4.1         0.68                                        Example 47                                                                            ˜25     12.1        0.49                                        Example 48                                                                            ˜25.0   6.3         ˜0.25                                 Example 49                                                                            >25.0         6.3         >0.25                                       Example 50                                                                            6.05          7.4         1.22                                        Example 51                                                                            6.12          7.4         1.21                                        Example 52                                                                            7.5           9.4         1.26                                        Example 53                                                                            2.0           9.4         4.75                                        Example 54                                                                            ˜12.5   8.0         ˜0.64                                 Example 55                                                                            ˜10.0   8.0         ˜0.80                                 Example 56                                                                            >12.5         7.5         <0.60                                       Example 57                                                                            7.18          7.5         1.04                                        Example 58                                                                            13.6          8.8         0.65                                        Example 59                                                                            4.8           8.5         1.77                                        Example 60                                                                            1.8           9.2         5.20                                        Example 61                                                                            2.1           9.2         4.42                                        ______________________________________                                    

EXPERIMENT 2 Inhibition of Gastric Secretion

In accordance with the method disclosed in Shay, H., et al.,Gastroenterology 5, 43-61(1945), Experiment 2 was carried out.

Sprague-Dawley rats having a body weight of 170±10 g were divided into 3groups(n=5) and deprived of food for 24 hours before the experiment withfree access to water. Under ether anesthesia, the abdomen was incised,and the pylorus was ligated. As a comparative group, Group 1 wasadministered intraduodenally in a volume of 0.5 ml/200 g of 30% aqueouspolyethylene glycol 400 solution. Groups 2 and 3 were administeredintraduodenally with the compound of Example 34 and omeprazole,respectively, each of which was suspended in 30% aqueous polyethyleneglycol 400 solution at a concentration of 20 mg/kg. After closing theabdominal cavity, the rats were placed for 5 hours and then killed bycervical dislocation. The stomach was extracted to obtain gastric juice.

The gastric juice was centrifuged at 1,000 g to remove precipitates. Theamount and acidity of the gastric juice were measured. Relative volumes,relative acid concentrations and relative acid outputs of the testcompounds were calculated from equations(I), (II) and (III) and theresults are shown in Table 2.

    ______________________________________                                        Relative volume                                                               (I) = the average amount of gastric juice of Group 1 - the                    average amount of gastric juice of Group 2)/(the average                      amount of gastric juice of Group 1 - the average amount                       of gastric juice of Group 3)                                                  Relative acid concentration                                                   (II) = (the average acidity of Group 1 - the average                          acidity of Group 2)/(the average acidity of Group 1 - the average             acidity of Group 3)                                                           Relative acid output                                                          (III) = (the total amount of acid output of Group 1 - the                     total amount of acid output of Group 2)/(the total amount of acid             output of Group 1 - the total amount of acid output of Group                  ______________________________________                                        3).                                                                       

                  TABLE 2                                                         ______________________________________                                        The amount and acidity of the gastric juice                                             Rel. Vol.    Rel. Conc.                                                                             Relative                                      Compound  (%)          (%)      Acid Output                                   ______________________________________                                        Example 18                                                                              0.38         0.02     0.29                                          Example 19                                                                              1.03         0.28     0.68                                          Example 20                                                                              1.28         0.64     0.92                                          Example 21                                                                              0.74         -0.04    0.38                                          Example 22                                                                              0.74         0.43     0.64                                          Example 23                                                                              0.39         0.42     0.44                                          Example 24                                                                              0.47         0.07     0.36                                          Example 25                                                                              0.69         0.14     0.50                                          Example 26                                                                              0.38         0.04     0.25                                          Example 27                                                                              0.29         0.12     0.30                                          Example 28                                                                              0.67         0.37     0.64                                          Example 29                                                                              0.87         0.67     0.84                                          Example 30                                                                              0.76         0.53     0.76                                          Example 31                                                                              0.86         0.74     0.79                                          Example 32                                                                              0.47         0.16     0.43                                          Example 33                                                                              1.09         0.34     0.79                                          Example 34                                                                              1.36         0.55     0.97                                          Example 35                                                                              0.92         0.58     0.79                                          Example 36                                                                              0.82         0.42     0.67                                          Example 37                                                                              0.37         0.15     0.37                                          Example 38                                                                              0.80         0.53     0.83                                          Example 39                                                                              0.66         0.22     0.57                                          Example 40                                                                              0.73         0.76     0.82                                          Example 41                                                                              0.63         0.15     0.48                                          Example 42                                                                              0.40         0.14     0.42                                          Example 43                                                                              0.81         0.44     0.76                                          Example 44                                                                              0.73         0.56     0.75                                          Example 45                                                                              0.20         -0.22    -0.06                                         Example 46                                                                              0.42         -0.21    0.11                                          Example 47                                                                              0.45         0.15     0.33                                          Example 48                                                                              0.75         0.52     0.76                                          Example 49                                                                              0.59         0.12     0.42                                          Example 50                                                                              0.85         0.65     0.82                                          Example 51                                                                              0.86         0.64     0.82                                          Example 52                                                                              1.03         0.55     0.79                                          Example 53                                                                              1.01         0.65     0.92                                          Example 54                                                                              0.94         0.35     0.82                                          Example 55                                                                              0.57                  0.50                                          Example 56                                                                              0.91         0.70     0.85                                          Example 57                                                                              0.92         0.35     0.67                                          Example 58                                                                              1.32         0.71     0.94                                          Example 59                                                                              1.53         0.47     0.83                                          Example 60                                                                              1.03         0.55     0.84                                          Example 61                                                                              0.73         0.51     0.76                                          ______________________________________                                    

EXPERIMENT 3 Anti-Secretory Effects

In accordance with the method see Ghosh and Shild, et al., BritishJournal of pharmacology 13:54-61 (1958)!, anti-secretory effects of thetest substances were studied in this Experiment.

3-1: Anti-Secretory Effects of the Test Substances When GastricSecretion is Stimulated by Histamine

Sprague-Dawley male rats having a body weight of 200±20 g were dividedinto 3 groups, Group 1 to be administered with the compound of Example34, Group 2 to be administered with SK&F96067 see Keeling, D. J., etal., Biochemical pharmacology 42, 1, 123-130(1991)! and Group 3 to beadministered with omeprazole. The rats of each Group, deprived of foodfor 24 hours before the experiment with free access to water, wereanesthetized by intraperitoneally administering of 1.5 g/kg of 20%aqueous urethane solution and positioned on the test plate which washeated and maintained at 37° C. The anesthetized rats were cannulated atthe right jugular vein for the administration of the test compounds andthe left jugular vein for the administration of stimulating substances.After an abdominal incision, tubes were inserted into the esophagus andduodenum, each of which was connected with saline in a thermostat and afraction collector. The esophagus and duodenum were perfused with salineat a rate of 1 ml/min from the thermostat by means of a peristalticpump.

To the right jugular vein, were administered the compound prepared inExample 34 and, as comparative compounds, SK&F96067 and omeprazole, eachof which was dissolved in ethanol, 40% polyethylene glycol or saline,respectively. To the left jugular vein, histamine was administered as agastric secretion stimulator.

The stomach was first perfused with saline and the perfusates containingthe gastric juice were collected at an interval of 10 minutes by meansof the fraction collector. When the gastric secretion reached to anequilibrium state, which took more than 60 minutes, histamine wasinfused at a dosage of 4 mg/2 ml/200 g/hr to stimulate the gastricsecretion, while collecting the perfusates for 60 minutes at an intervalof 10 minutes.

While histamine was continuously being infused, the compound prepared inExample 34, SK&F96067 and omeprazole of different concentrations asrepresented in Table 3 were intravenously injected into the rightjugular vein to Groups 1, 2 and 3, respectively; and then the perfusateswere collected. The volume and acidity of the fractions collected weremeasured to calculate the acid output in μM/10 min.

The gastric secretion inhibition (%) of the test compounds wascalculated from the following equation:

    The gastric secretion inhibition (%) of the test compounds =(A-C)/(A-B)×100 . . .                              (IV)

in which

A is the gastric acid output(μmol/10 min) of the fraction collected 60mins after the administration of histamine;

B is the gastric acid output(μmol/10 min) of the fraction collected 60minutes after the perfusion with saline; and

C is the minimum gastric acid output(μmol/10min) during the period of120 minutes after the administration of the test compounds.

The results are shown in Table

                  TABLE 3-1                                                       ______________________________________                                        The gastric secretion inhibition (%)                                                                           Compound of                                  Amount (mg/kg)                                                                           Omeprazole SK&F96067  Example 34                                   ______________________________________                                        0.1         8.0%                                                              0.3         49.4%                                                             0.5                   29.8%      44.4%                                        1.0        102.3%     57.1%      52.0%                                        3.0                   75.9%      76.5%                                        ED.sub.50   0.29 mg/kg                                                                               0.96 mg/kg                                                                               0.90 mg/kg                                  ______________________________________                                    

3-2: Inhibition of Gastric Secretion by the Test Substances in case theGastric Secretion is Stimulated by Pentagastrin

The same procedures as in Experiment 3-1 were carried out, except thatas a secretion stimulating substance, pentagastrin was infused into theleft jugular vein of the rats at a dosage of 24 μg/2 ml/200 g/hr. Theresults of the experiment are shown in Table 3-2.

                  TABLE 3-2                                                       ______________________________________                                        The gastric secretion inhibition (5) and ED.sub.50                            when the secretion is stimulated by histamine                                                                  Compound of                                  Amount (mg/kg)                                                                           Omeprazole SK&F96067  Example 34                                   ______________________________________                                        0.1                                                                           0.3         5.0%                                                              0.5         63.1%                                                             1.0        114.3%     32.6%       41.2%                                       3.0                   64.0%       77.0%                                       5.0                   77.3%      110.2%                                       ED.sub.50   0.47 mg/kg                                                                               1.85 mg/kg                                                                               1.31 mg/kg                                  ______________________________________                                    

EXPERIMENT 4 Reversibility Test

4-1: Preparation of Gastric Vesicles

Gastric vesicles were prepared from pig stomach by the method describedin Saccomani G., et al., J. Biol. Chem. 250, 4802-4809 (1975). Thevesicles were lyophilized and kept at -70° C. The protein content wasdetermined by the method of Lowry et al., using bovine serum albumin asstandard see Lowry, O. H., Rosebrough, N. J. and Randall, R. J., J.Biol. Chem. 193, 265-275 (1951)!.

4-2: Determination of H⁺ /K⁺ ATPase Activity

Test tubes were divided into 4 groups, each having 3 test tubes. As acontrol group, group 1 was added with the 10 μl of DMSO. Groups 2, 3 and4 were administered with the compound prepared in example 34 whose finalconcentration are 0.17 μM, 0.33 μM and 0.67 μM, respectively. Each groupwas further divided into 3 small groups, in which enzymes were activatedby ATP; ATP and Mg⁺⁺ ; and ATP, Mg⁺⁺ and K⁺, respectively.

To all of the test tubes, were added 100 μl of lyophilized vesiclesprepared at the concentration of 25 μg protein/ml and then 90 μl of 5 mMPipes/Tris buffer pH 7.0. The compound prepared in Example 34 was addedto each Group until the final concentration thereof became 0.17, 0.33 or0.67 μM, respectively, They were preincubated for 15 minutes.

50 μl of ATP(3 mM) was added to each of the four Groups and the 50 μl ofMgCl₂ (2 mM) was added only to the 2nd and 3rd small groups of allGroups. Further, to the 3rd small groups of all Groups, were added 50 μlof KCl solution of various concentrations(from 0.1 mM to 30 mM) and then150μl of Pipes/Tris buffer of pH 7.0. To the rest small groups,Pipes/Tris buffer of pH 7.0 was added until the volume became the sameas that of the 3rd small group.

The test tube's were incubated at 37° C. for 30 minutes and then thereaction was terminated by adding 25% cold trichloroacetic acidsolution. They were centrifuged by means of a microcentrifuge and thesupernatant was taken up for the measurement of the released inorganicphosphate content by an automatic analyzer(CIBA CORNING, Express 550).

In accordance with the same procedures as above, except that 15 and 30μm of omeprazole and 0.75, 1.5 and 3.0 μm of SK&F96067 were used ascomparative substances, released inorganic phosphate content wasmeasured.

The released inorganic phosphate contents of the three small groups wereconsidered as the activity of H⁺ /K⁺ ATPase at each of theconcentrations employed. The specific activity of H⁺ /K⁺ ATPase wascalculated from the following equation:

    Specific activity=(A-C)-(B-C) . . .                        (V)

in which

A is the activity of enzyme activated by ATP, Mg⁺⁺ and , K⁺ ;

B is the activity of enzyme activated by ATP and M⁺⁺ and

C is the activity of enzyme activated by ATP.

The specific activity, thus calculated, of Groups 1, 2, 3 and 4 whichemployed DMSO and the compound of Example 34 at 3 differentconcentrations were then plotted with respect to the concentration ofKCl in FIG. 1 according to the method of Lineweaver-Burk, wherein ▪, □and ◯ represent the respective concentrations of the compound of Example34 of 0.67 μM, 0.33 μM and 0.17 μM; and  represents concentration ofthe DMSO compound. FIG. 2 depicts the Lineweaver-Burk plot of thespecific activities obtained from SK&F96067, wherein ▪, □ and ◯represent its respective concentrations of 3.0 μM, 1.5 μM, 0.75 μM; and represents concentration of the DMSO compound. FIG. 3 illustrates theLineweaver-Burk plot of the specific activities obtained fromomeprazole, wherein  and □ represent its concentrations of 15 μM and 30μM; and ◯ represents the concentration of DMSO.

As can be seen from FIGS. 1, 2 and 3, the compound of the presentinvention and SK&F96067 inhibited competitively with K⁺ at the K⁺binding site of proton pump, whereas omeprazole did not inhibitcompetitively. Namely, in the case of the compound of the presentinvention and SK&F96067, V_(max) in the Lineweaver-Burk plot was notchanged, whereas K_(m) value was changed. The Ki values of the presentinvention compound and SK&F96067 were 0.04 μM and 0.7 μM, respectively.In contrast, in the case of omeprazole, the reaction speed was greatlyreduced in comparison with the control values at the concentrations of15 and 30 μM; and the inhibition of the enzyme activity was not overcomeby increasing the concentration of KCl. In view of this, it wasconfirmed that omeprazole was not competitive inhibition relationshipwith K⁺.

4-3: Reversibility of Inhibition

The inhibition mechanism of proton pump activity by the presentinvention compound was tested in accordance with the so-called Dilutionand Washout method see D. J. Keeling, et al., Biochemical Pharmacology42(1) 123-130(1991)!.

Namely, test tubes were divided into two group, groups 1 and 2 to beadministered with DMSO and the compound prepared in Example 34,respectively. 10 μl of each of DMSO and the compound(6 μM) prepared inExample 34 was added to groups 1 and 2, respectively.

To all two groups, was added 100 μl of lyophilized vesicles prepared inExperiment 4-1 at the concentration of 100 μg protein 1 ml. Then, 5 mMPipes/Tris buffer(pH 6.4 ) was added to the three groups until thevolume of test tubes became 150 μl. After the preincubation for 15minutes, H⁺ /K⁺ ATPase activity was measured in accordance with the sameprocedures as in Experiment 4-2. The concentrations of the testsubstances as indicated above are the final concentrations.

After the completion of preincubation, each group was diluted 50 timeswith 5 mM Pipes/Tris buffer(pH 6.4), and then centrifuged for 60 minutesby means of Beckman ultracentrifuge(Model L8-80). The supernatant wasdiscarded and the pellet was suspended with 5 mM Pipes/Tris buffer pH6.4 until the volume became the same as the preincubation volume.Thereafter, the inhibition of (H⁺ +K⁺)-ATPase activity was measured inaccordance with the same procedures as in Experiment 4-2; and it wasfurther measured in accordance with the same procedures as above, exceptthe 60 μM omeprazole and 60 μM SK&F96067 were used as comparativesubstances. The inhibition of H⁺ /K⁺ ATPase activity before and afterthe Dilution and Washout procedures is shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        The inhibition of H.sup.+ /K.sup.+ ATPase activity                                        Before Dilution                                                                        After Dilution                                                       and Washout                                                                            and Washout                                              ______________________________________                                        Compound of   84(%)      16(%)                                                Example 34                                                                    Omeprazole    80(%)      67(%)                                                SK&F96067     80(%)       0(%)                                                ______________________________________                                    

As can be seen from Table 4, omeprazole inhibited 80% of the enzymeactivity before the Dilution and Washout procedure and 67% of theactivity even after the Dilution and Washout procedure. This shows thatomeprazole did not leave the binding sites of the enzyme after theDilution and Washout procedure, indicating that the inhibition byomeprazole is irreversible.

In contrast, SK&F96067 and the present invention compound inhibited 80%and 84%, respectively, of the enzyme activity before the Dilution andWashout procedure, whereas they showed no or 16% of inhibition of theenzyme activity after the Dilution and Washout procedure. This indicatesthat the inhibition of the enzyme activity of SK&F96067 and the presentinvention compound is reversible.

While the invention has been described with respect to the abovespecific embodiments only, other modifications and variations may bemade without departing from the spirit and scope of the presentinvention as set forth in the following claims.

What is claimed is:
 1. A quinazoline derivative represented byformula(I) and a pharmaceutically acceptable salt thereof: ##STR4##wherein R₁ and R₂ are each hydrogen or a C₁ -C₄ alkyl group;R₃ ishydrogen or a halogen; R₄, R₅, R₆, R₇, R₈ and R₉, which may be the sameor different, are each hydrogen, a C₁ -C₄ alkyl group, a cyclopropylgroup, or a C₁ -C₄ alkyl group substituted with a halogen; and R₁₀ is amethoxy group.
 2. The quinazoline derivative of claim 1, which isselected from the groupconsisting8-methoxy-2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline8-methoxy-(N-methylphenylamino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline; 8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) quinazoline;8-methoxy-2-(4-fluoro-N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) quinazoline;8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;(R)-8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline; (S)-8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) quinazoline;8-methoxy-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluoro-N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline; 2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(1-fluoromethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-fluoro-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluorophenylamino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(2-methyl-4-fluorophenylamino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(3-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(3-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluorophenylamino)-8-methoxy-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluorophenylamino)-4-(1,8-ethano-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;8-methoxy-2-(4-fluoro-2-methylphenylamino)-4-(1,8-ethano-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;2-(4-fluoro-2-methylphenylamino)-8-methoxy-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline;and a pharmaceutically acceptable salt thereof.
 3. The pharmaceuticallyacceptable salt of the quinazoline derivative of claim 1, which isselected from the group consisting of hydrochloride, sulfate, phosphate,nitrate, tartrate, fumarate, citrate, mesylate and acetate salts.
 4. Aprocess for preparing quinazoline derivatives of formula(I) defined inclaim 1, which comprises reacting a compound of formula(II) with acompound of formula(III) to give a compound of formula(IV), which isthen reacted with a compound of formula(V): ##STR5## wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ have the same meanings as defined inclaim 1, and X is chlorine.
 5. The process of claim 4, where thereaction of the compound of formula(II) with the compound offormula(III) is carried out in a solvent selected from the groupconsisting of dichloromethane, acetone, acetonitrile, tetrahydrofuranand a mixture thereof with water, and a base selected from the groupconsisting of triethylamine, N,N-dimethylaniline and pyridine.
 6. A2-chloro-4-(1-substituted-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazolineof formula(IV): ##STR6## wherein R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀ havethe same meanings as defined in claim 1, and X is chlorine.
 7. A processfor preparing a compound of formula (IV), which comprises reacting acompound of formula(II) and a compound of formula(III): ##STR7## whereinR₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ have the same meanings as defined inclaim 1, and X is chlorine.
 8. The process of claim 7, where thereaction is carried out in a solvent selected from the group consistingof dimethylformamide, p-dioxane and dimethyl-sulfoxide.
 9. Apharmaceutical composition for treating peptic ulcer, which comprises atherapeutically effective amount of the quinazoline derivative orpharmaceutically acceptable salt thereof recited in claim 1 and apharmaceutically acceptable carrier.